The tripeptide glutathione (2-amino-5-{[2-[(carboxymethyl)amino]-1-(mercaptomethyl)-2-oxoethyl]amino}-5-oxopentanoic acid, or γ-glutamylcysteinylglycine) is considered one of the major anti-oxidants of the human body, with cellular concentrations in the millimolar range. A number of enzyme systems exist that are dedicated to maintaining glutathione homeostasis, including the rate-limiting enzyme for its synthesis, γ (gamma)-glutamylcysteine synthetase, and glutathione reductase, which reduces GSSG, using NADPH as a cofactor. Glutathione may serve a major role in maintaining the reduced state of cellular protein thiol groups. It can accomplish this role through the function of glutathione peroxidases, which utilize GSH to reduce hydroperoxides. In addition, upon oxidative stress, glutathione often spontaneously forms mixed disulfides with protein thiol groups, causing reversible S-glutathionylation.
S-glutathionylation of thiols may confer protection against their irreversible oxidation, like for instance the formation of sulphonic acid moieties. If the targeted cysteine is a functionally critical amino acid, S-glutathionylation may also modify protein function. For instance S-glutathionylation of the p50 subunit of NF-κB (NF-kappaB) as well as of the c-Jun subunit of AP-1 may be linked to repression of DNA binding activity of these transcription factors. The activities of protein kinase C, glyceraldehyde-3-phosphate dehydrogenase, and HIV-1 protease may also be adversely affected by S-glutathionylation.
Mammalian glutaredoxins (GRX), or thioltransferases, are members of the thiol-disulfide oxidoreductase family. They are often characterized by a thioredoxin fold and a Cys-Pro-Tyr(Phe)-Cys active site. Examples include GRX1, a cytosolic protein, and GRX2, which may be directed to the mitochondria by a mitochondrial leader sequence and/or can also occur in the nucleus following alternative splicing. Mammalian glutaredoxins may specifically catalyze the reversible reduction of protein-glutathionyl-mixed disulfides to free sulfhydryl groups, using GSH as a cofactor. GRXs through their deglutathionylation activity could therefore play a unique role in redox signaling.